Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease.

Abstract

Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)-induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.

• Authors: Huiping Shi, Bojing Shao, Liang Gao, Thamizhiniyan Venkatesan, John Michael McDaniel, Meixiang Zhou, Samuel McGee, Pengchun Yu, Jasimuddin Ahamed, Janna Journeycake, James N George, Lijun Xia
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 34 Pg. e2207592119 (08 23 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 35969769 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• von Willebrand Factor
• ADAMTS13 Protein

Topics

• ADAMTS13 Protein (metabolism, pharmacology, therapeutic use)
• Anemia, Sickle Cell
• Animals
• Disease Models, Animal
• Endothelial Cells (metabolism)
• Gene Deletion
• Hemolysis (drug effects)
• Inflammation (drug therapy, metabolism)
• Mice
• Vascular Diseases (drug therapy, etiology)
• von Willebrand Factor (genetics, metabolism)